Anemia may be chronic (e.g., anemia due to chronic kidney disease, anemia due to chronic heart failure, idiopathic anemia of aging, anemia of chronic disease, such as inflammatory bowel disease or rheumatoid arthritis, myelodysplastic syndrome, bone marrow fibrosis, and other aplastic or dysplastic anemias), subacute (e.g., chemotherapy induced anemia, such as chemotherapy for treating cancer, hepatitis C, or other chronic disease that reduces bone marrow production), acute (e.g., blood loss from injury or surgery), nutrition related (e.g., iron deficiency or vitamin B12 deficiency), or hemaglobinpathies (e.g., sickle cell disease, thalassemia, etc.). Hypoxia inducible factor (HIF) prolyl hydroxylase inhibitor is a novel drug for treating anemia. These drugs work by stabilizing HIF compounds and stimulating endogenous erythropoietin.
{[5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl] amino} acetic acid, known as vadadustat, is developed by Akebia. vadadustat is an HIF prolyl hydroxylase inhibitor and has the function of treating or preventing anemia. The clinical trial of vadadustat for treatment of anemia due to chronic kidney disease is in Phase III. Its structure is shown in Formula (I).

Different crystalline forms of solid chemical drugs can lead to differences in their solubility, stability, flowability and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compounds (see K. Knapman, Modern Drug Discovery, 3, 53-54, 57, 2000.), which resulting in differences in clinical efficacy. The discovery of new crystalline forms (including anhydrates, hydrates, solvates, etc.) of the active pharmaceutical ingredients may provide drug substance with processing advantages and better physical and chemical properties such as better bioavailability, better storage stability, easiness to process, and easiness to purify. Some novel crystalline forms may serve as intermediate crystal forms to facilitate solid state transformation to desired forms. Novel polymorphs of raw materials can enhance the performance of the drug and provide more solid states in the formulation, such as improving dissolution and storage life, and making it easier to process.
Crystalline Form A, Form B and Form C of vadadustat were disclosed in WO2015073779. As disclosed in the specification, Form B is metastable and may convert to Form A in slurry at high temperature. It is found by the inventors of the present disclosure that the preparation repeatability of Form C is poor. WO2015073779 also disclosed that form A is suitable for the preparation of pharmaceutical formulations. However, other important properties such as stability and solubility in biological media were not mentioned. Therefore, it is still necessary to systematically develop different crystalline forms of vadadustat, to find novel crystalline forms more suitable for drug development, and to promote the preparation of better pharmaceutical formulations of the active pharmaceutical ingredients.
The present disclosure provides crystalline form CS1, form CS2 and Form CS8. Crystalline forms of the present disclosure can be easily made and have advantages in stability, hygroscopicity, solubility, mechanical stability, pressure stability, formulation stability and processing performance, which provides new and better choices for the preparation of pharmaceutical formulations containing vadadustat and is of great significance for drug development.